Inflammation is involved in the pathogenesis of various diseases, encompassing autoimmunity, viral infections and cancer. A number of inflammatory autoimmune diseases are known, including psoriatic arthritis, diabetes and rheumatoid arthritis (RA). RA is characterized by systemic inflammation, accumulation of mononuclear cells in the synovium and impaired immunological tolerance.
Monoclonal antibodies (mAbs) targeting CD3 have been demonstrated to induce immune tolerance in some autoimmune diseases. Intact mAbs, although mitogenic, can establish long-term tolerance and stabilization of disease progression in patients recently diagnosed with type 1 diabetes mellitus (T1DM) and in the NOD and experimental autoimmune encephalomyelitis (EAE) mouse models of autoimmunity. The therapeutic effects of CD3-specific mAbs have been observed with the administration of modified antibodies or F(Ab)2 fragments. The modified antibodies Teplizumab and Otelixizumab have been tested in T1 DM, these antibodies are not mitogenic and reduce the incidence and severity of cytokine release.
However, despite promising results from animal model and pre-clinical data, there has been limited success in using anti-CD3 therapy in humans. For example clinical trials using anti-CD3 therapy for RA have currently been stopped due to low efficacy. There have also been some problems in trials against diabetes, again due to inefficiency and dosage problems: http://clinicaltrials.gov/ct2/show/results/NCT00378508 http://www.genengnews.com/gen-news-high lights/macrogenics-and-lilly-ponder-future-of-diabetes-mab-after-phase-iii-flop/81244098/.
There is therefore a need for improved therapies for inflammatory and autoimmune diseases.